N-methyl-d-glucosamine and derivatives thereof



. positive organisms may Patented Jan. 16, 1951 N-METHYL-d-GLUCOSAMINEAND 'DERIVATIVES THEREOF.

Frederick A. Kuehl, J12, Westfield, N. J., assignor to Merck & (30.,Zinc., Rahway, N. J., a corporation of New Jersey No Drawing.Application February 1 1946, Serial No. 645,008

8 Claims.

This invention relatesto certain new chemical compounds, and to certainnew and improved procedures by'which they maybe prepared from readilyavailable starting materials. More particularly, it relates to the newchemical com: pound N-methyl-d-glucosamine, and to various acylderivatives thereof. These compounds are potentially useful in thepreparation of antibiotics which are therapeutically active againstAmong such grambe mentioned Bacillus mycoides and Bacillus cereus.Gram-negative organisms against which said antibiotics may possesstherapeutic activity include Pseuclomonas fluorescens, Pseudomonasaeruginosa, and Serratia, marcescens. These new chemicalcomgram-positive organisms.

spoundslmaybe readily prepared by utilizing the known chemical compoundd-glucosamine as the starting material.

In the preparation of N-methyhd-glucosamine I treat d-glucosamine with amethylatingagent. Among suitable methylating agents, dimethyl A sulfatehas been found most satisfactory.

The resulting N-methyl-d-glucosamine may then readily be converted to amixture of the a and 18 forms of the pentaacetyl derivatives of N-methyl-d-glucosamine by acetylation. Ordinarily it is preferred to carryout the acetylation using, as the aeetylating agent, a mixture ofpyridine and acetic anhydride. When the mixture of the a and c isomersis treated with zinc chloride and acetic anhydride, the mixture isconverted predominantly to the a form, which may then be recovered insubstantially pure form by recrystallization from methanol and/or bychromatographic methods using acid-washed alumina as the adsorbent.

My improved process for making N-methyl-dglucosamine, and its pentaacylderivatives, will be clear from the following example, which is intendedto be illustrative but not restrictive.

Example grams of d-glucosamine hydrochloride were dissolved in 25 cc. of1.0 N sodium hydroxide solution. The solution was then shaken with 2.5cc. of dimethyl sulfate at room temperature for one-half hour. Theresulting solution was then concentrated to dryness, and the residuetriturated with 10 cc. of alcohol. It was then filtered. The alcoholsoluble material was then acetylated using a mixture of 30 cc. ofpyridine and 20 cc. of acetic anhydride as the acetylating agent. Thisstep was carried out at room temperature, while allowing the mixture toSta d overnight.

.glucosamine. The melting point The solvents were then removed underreduced pressure less than atmospheric, and the residue duced pressure,and the residue dissolved in about 20 cc. of water. It was thenextracted with chloroform from this aqueous solution.

The chloroform extract was washed, successively, with aqueous sodiumbicarbonate, dilute hydrochloric acid and water. An ether solution ofthe chloroformresidue deposited 2.4 grams of crystalsconsistingsubstantially of a mixture of the a ands 'forms ofN-methyl-pentaacetyl-dof the product was -146 C. and the specificrotation (a) =99 (concentration 0.7% in chloroform).

The product was purified by alternate recrystallizations from a mixtureof about 5 cc. of chloroform and about 20 cc. of ethyl. ether, the finalrecrystallization being from methanol. It was then chromatographed inether-chloroform solution (1:1) on acid-washed alumina, theether-chloroform solution passing through alumina yielding the purepentaacetyl N- methyl-a-dglucosamine having a. melting point of1605-1615 C. Specific rotation was (concentration 0.6% in chloroform).

It is obvious that various changes and modifications might be made in myinvention as described without departing from the scope thereof asdefined in the appended claims.

I claim:

1. The process of recovering substantially pure pentaacetyl-N-methyl-ad-glucos-amine from a mixture of this compound with pentaacetyl N-methyl-B d-glucosamine which comprises recrystallizing the desiredcompound from a mixture of chloroform and ethyl ether, againrecrystallizing the desired compound from methanol dissolving saidcompound in 1:1 chloroform-ethyl ether, and then securing the desiredcompound from the mixture by chromatographic separation on acid-washedalumina.

2. The process of converting a mixture of the a and ,8 isomers ofpentaacetyl-N-methyl-d-glucosamine to a form in which the c isomerpredominates which comprises treating said mixture with zinc chlorideand acetic anhydride.

3. The process of recovering substantially purepentaacetyl-N-InethyLa-d-glucosamine from a mixture of said isomer withpentaacetyl-N methyl-fl-d-glucosamine which comprises treating saidmixture with zinc chloride and acetic anhydride in order to convert saidmixture to one in which said a-isomer predominates, and securing saidsubstantially pure pentaacetyl-N- methyl-a d-glucosamine from saidproduct by repeated crystallization.

4. The process of recovering substantially pure pentaacetyl-N-methyl-cd-glucosamine from a mixture of said isomer with pentaacetyhN- methyla-d-glucosamine which comprises treating said mixture with zinc chlorideand acetic anhydride in order to convert said mixture to one in whichsaid a-isomer predominates dissolving said mixture in 1:1chloroform-ethyl ether, and securing said substantially purepentaacetyla-d-N-methyl glucosamine from said resulting mixture bychromatography on acid-Washed alumina.

5. The process of recovering substantially pure pentaacetyl-N-methyl-a.d-glucosamine from a mixture of said isomer with pentaacetyl-N-methy1-,8 d-glucosamine which comprises treating said mixture With zincchloride and acetic anhydride in order to convert said mixture to one inwhich said a-isomer predominates, and securing said substantially purepentaacetyl-N- methyl 0. d-glucosamine from said product by repeatedcrystallization, from a chloroform-ethyl ether mixture and frommethanol.

6. The process for the preparation of pentaacetyl N-methyl-a-dglucosamine which comprises treating a salt of d-glucosamine with amethylating agent, said reaction being carried out in an alkalinesolution and at room temperature, concentrating the resulting solution,dissolving the residue in alcohol, acetylating the alcohol solublematerial in the presence of pyridine, heating the acetylation productwith zinc chloride and acetic anhydride and recovering pentaacetylN-methyl-a-d-glucosamine.

7. The process for the preparation of pentaacetylN-methyl-a-d-glucosamine which comprises treating a salt ofd-glucosamine with dimethyl sulfate, said reaction being carried out inan alkaline solution and at room temperature, concentrating theresulting solution, dissolving the residue in alcohol, acetylating theal cohcl soluble material in the presence of pyridine, heating theacetylation product with zinc chloride and acetic anhydride andrecovering pentaacetyl N-methyl-a-d-glucosamine.

8. The process for the preparation of pentaacetyl N-methyl-d-glucosamine which comprises treating a salt of d-glucosaminewith dimethyl sulfate in an alkaline solution and at room temperature,concentrating the resulting solution, dissolving the residue in alcoholand acetylating the alcohol soluble material in the presence of pyridineto produce pentaacetyl N-methyl d-glucosamine.

FREDERICK A. KUE HL, JR.

REFERENCES CITED The following references are of record in the file ofthis patent:

vol. 37, (1915) pages

4. THE PROCESS OF RECOVERING SUBSTANTIALLY PURE PENTAACETYL-N-METHYL-BD-GLUCOSAMINE FROM A MIXTURE OF SAID ISOMER WITH PENTAACETYL-NMETHYL A-DGLUCOSAMINE WHICH COMPRISES TREATING SAID MIXTURE WITH ZINC CHLORIDE ANDACETIC ANHYDRIDE IN ORDER TO CONVERT SAID MIXTURE TO ONE IN WHICH SAIDA-ISOMER PREDOMINATES DISSOLVING SAID MIXTURE IN 1:1 CHLOROFORM-ETHYLETHER, AND SECURING SAID SUBSTANTIALLY PURE PENTAACETYLA-D-N-METHYLGLUCOSAMINE FROM SAID RESULTING MIXTURE BY CHROMATOGRAPHY ON ACID-WASHEDALUMINA.
 8. THE PROCESS FOR THE PREPARATION OF PENTAACETYLN-METHYL-D-GLUCOSAMINE WHICH COMPRISES TREATING A SALT OF D-GLUCOSAMINEWITH DIMETHYL SULFATE IN AN ALKALINE SOLUTION AND AT ROOM TEMPERATURE,CONCENTRATING THE RESULTING SOLUTION, DISSOLVING THE RESIDUE IN ALCOHOLAND ACETYLATING THE ALCOHOL SOLUBLE MATERIAL IN THE PRESENCE OF PYRIDINETO PRODUCE PENTAACETYL-N-METHYL D-GLUCOSAMINE.